ABSTRACT: In utero exposure to diesel exhaust particulates is associated with an altered cardiac transcriptional response to transverse aortic constriction and altered DNA methylation.
Project description:In utero exposure to diesel exhaust particulates has been associated with increased adult susceptibility to heart failure in mice but the mechanisms by which this exposure promotes susceptibility are poorly understood. To identify potential transcriptional effects that mediate this susceptibility, we have performed RNA-seq analysis on adult hearts from mice exposed to diesel exhaust in utero and that have subsequently undergone transverse aortic constriction. We identified three target genes, Mir133a-2, Ptprf and Pamr1, which demonstrate dysregulation after exposure and aortic constriction. Examination of expression patterns in human heart tissue indicate a correlation between expression and heart failure. We subsequently examined for DNA methylation modifications at these candidate loci in neonatal cultured cardiac myocytes after in utero exposure to diesel exhaust and found that the promoter for Mir133a-2 is differentially methylated.
Project description:Developmental exposure to particulate matter air pollution is harmful to cardiovascular health, but the mechanisms by which this exposure mediates susceptibility to heart disease is poorly understood. We have previously shown, in a mouse model, that gestational exposure to diesel exhaust results in increased cardiac hypertrophy, fibrosis and susceptibility to heart failure in the adult offspring following transverse aortic constriction. In this study we have found hypomethylation of DNA in neonatal cardiomyocytes isolated from in utero DE exposed neonates. We have demonstrated that in utero exposure to diesel exhaust alters the neonatal cardiomyocyte transcriptional and epigenetic landscapes, as well as the metabolic capability of these cells. Understanding how exposure alters the developing heart through dysregulation of gene expression, metabolism and DNA methylation is vital for identifying therapeutic interventions for air pollution-related heart failure.
Project description:Developmental exposure to particulate matter air pollution is harmful to cardiovascular health, but the mechanisms by which this exposure mediates susceptibility to heart disease is poorly understood. We have previously shown, in a mouse model, that gestational exposure to diesel exhaust results in increased cardiac hypertrophy, fibrosis and susceptibility to heart failure in the adult offspring following transverse aortic constriction. In this study, we have analyzed gene expression in neonatal cardiomyocytes after gestational exposure by RNA-sequencing and have identified 300 genes that are dysregulated, including many involved in cardiac metabolism.
Project description:Transcriptom analysis of microdissect adrenal medulla after 8 weeks of cardiac pressure overload caused by transverse aortic constriction. Comparative transcriptome analysis was determined using the GeneChip Mouse Genome 430 2.0 Array (Affymetrix, Santa Clara, CA, USA). Six microarrays from microdissected adrenal medulla of mice were performed 8 weeks after transverse aortic constriction or sham operation.
Project description:Transcriptom analysis of stellate sympathetic ganglia after 8 weeks of cardiac pressure overload caused by transverse aortic constriction. Comparative transcriptome analysis was determined using the GeneChip Mouse Genome 430 2.0 Array (Affymetrix, Santa Clara, CA, USA). Six microarrays from stellate sympathetic ganglia of mice were performed 8 weeks after transverse aortic constriction or sham operation.
Project description:Transcriptom analysis of stellate sympathetic ganglia after 8 weeks of cardiac pressure overload caused by transverse aortic constriction.
Project description:Transcriptom analysis of microdissect adrenal medulla after 8 weeks of cardiac pressure overload caused by transverse aortic constriction.
Project description:Air pollution is an environmental risk factor linked to multiple human diseases including cardiovascular diseases (CVDs). While particulate matter (PM) emitted by diesel exhaust damages multiple organ systems, heart disease is one of the most severe pathologies affected by PM. However, the in vivo effects of diesel exhaust particles (DEP) on the heart and the molecular mechanisms of DEP-induced heart dysfunction have not been investigated. In the current study, we attempted to identify the proteomic signatures of heart fibrosis caused by diesel exhaust particles (DEP) in CVDs-prone apolipoprotein E knockout (ApoE-/-) mice model using tandem mass tag (TMT)-based quantitative proteomic analysis. DEP exposure induced mild heart fibrosis in ApoE-/- mice compared with severe heart fibrosis in ApoE-/- mice that were treated with CVDs-inducing peptide, angiotensin II. TMT-based quantitative proteomic analysis of heart tissues between PBS- and DEP-treated ApoE-/- mice revealed significant upregulation of proteins associated with platelet activation and TGFβ-dependent pathways. Our data suggest that DEP exposure could induce heart fibrosis, potentially via platelet-related pathways and TGFβ induction, causing cardiac fibrosis and dysfunction.
Project description:By means of Operon V3 microarrrays, the in vivo, aortic endothelial transcriptomic responses to chronic (30 day) whole body exposure to diesel exhaust were assessed in wild type and Apo E (-/-) mice. The in vitro response of cultured Svec 4-10 cells exposed to a soluble extract extract of diesel engine particulate were similarly assessed.
